Pyridopyrimidones are versatile pharmacophores in medicinal chemistry. Their heterocyclic structure is found in several biologically active molecules. They also serve as key intermediates for the synthesis of several biologically active molecules, such as pyridoquinazoline inhibitors of receptor tyrosine kinases, CCKA receptor antagonists, anti-bacterial agents, inhibitors of human neutrophil elastase, diuretics, anti-hypertensives, angiotensin II antagonists, and anti-allergics. See for example Pyrido[2,3-d]pyrimidine angiotensin II antagonists. Ellingboe J. W., Antane M., Nguyen T. T., Collini M. D., Antane S., Bender R., Hartupee D., White V., McCallum J., Park C. H., et al. J Med Chem. 1994 Feb. 18; 37(4):542–50; Antihypertensive activity of 6-arylpyrido[2,3-d]pyrimidine-7-amine derivatives. Bennett L. R., Blankley C. J., Fleming R. W., Smith R. D., Tessman D. K. J Med Chem. 1981 April; 24(4):382–9; and Synthesis and structure-activity relationships of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids as antitumor agents. Part 1. Tomita K, Tsuzuki Y, Shibamori K, Tashima M, Kajikawa F, Sato Y, Kashimoto S, Chiba K, Hino K. J Med Chem. 2002 Dec. 5; 45(25):5564–75 and. Pyrimidones or molecules derived from pyrimidone cores are found in several active pharmaceutical products. Examples of such pharmaceutical products include Iressa® and Viagra®. See for example Improvements in Quality of Life and Disease-related Symptoms in Phase I Trials of the Selective Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 in Non-Small Cell Lung Cancer and Other Solid Tumors. LoRusso P. M., Herbst R. S., Rischin D., Ranson M., Calvert H., Raymond E., Kieback D., Kaye S., Gianni L., Harris A., Bjork T., Maddox A. M., Rothenberg M. L., Small E. J., Rubin E. H., Feyereislova A., Heyes A., Averbuch S. D., Ochs J., Baselga J. Clin Cancer Res. 2003 June; 9(6):2040–8 and Clinical Efficacy of sildenafil Citrate and Predictors of Long-term Response. Gonzalgo M. L., Brotzman M., Trock B. J., Geringer A. M., Burnett A. L., Jarow J. P. J Urol. 2003 August; 170 (2):503–506.
While there are various methods for making pyridopyrimidones, they often involve multiple steps and result of various side reactions. An example of one such method for making 2 substituted pyridopyrimidones is illustrated below:
Pursuant to this scheme, the acylation of 2-aminonicotinoate, with an appropriate benzoyl chloride is followed by ammonolysis of the ester. The intermediate bis-amide is then subjected to base promoted cyclization to obtain the desired pyrimidone.
Although this scheme provides a reasonable path to the desired pyrimidones, the conversion of intermediate Ia to intermediate Ib does suffer from bis-acylation as a major side reaction, and the conversion of intermediate Ib to intermediate Ic requires the use of ammonia under pressure.
Given the useful applications for pyridopyrimidones, it is desirable to have a facile route and method for their synthesis, in particular, routes and methods which yield minimal side reactions without unnecessary and sometimes problematic or toxic reagents.